Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: CNCCOC
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Solvent: CCN(CC)CC
Product: COCCN(C)CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (80 mg, 0.27 mmol) and (2-methoxyethyl)methylamine (450 mg, 5.04 mmol) are heated 100° C. for 2 h. Additional (2-methoxyethyl)methylamine is added and heating is continued for 1 hr. The reaction mixture is cooled and treated with triethylamine (10 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, MeOH-Chloroform). The product containing fractions are concentrated and triturated with EtOAc-hexane. The solid obtained is collected by filtration and dried to provide the title compound (55 mg, 53%) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[C:16]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(O)(C)C>[ClH:1].[C:16]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:15]=[CH:14][C:9]4[NH:10][C:11](=[O:13])[O:12][C:8]=4[CH:7]=3)[CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccc(CCCCCl)cc2o1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cl
Product: O=c1[nH]c2ccc(CCCCN3CCN(c4cccc5ccccc45)CC3)cc2o1
Yield: 497.9 %

Procedure:
To a 100 ml round-bottom flask equipped with condenser and nitrogen inlet were added 0.658 grams (3.10 mmol) of 6-(4-chlorobutyl)-benzoxazolone, 0.7 grams (3.10 mmol) of N-(1-naphthyl)piperazine, 0.328 grams sodium carbonate, 2 mg sodium iodide, and 50 ml isopropanol. The reaction was refluxed for 3 days, evaporated, taken up in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent, and the product dissolved in acetone, precipitated with ethereal HCl, and the white solid filtered, washed with acetone, and dried to afford 6.76 grams (46.0%) of a white solid, m.p. 231°-233° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[C:19]#[CH:20].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:18][C:19]#[C:20][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: C#CCOCCOCCOCCOCCO
Reactant: O=C(OCc1ccccc1)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cccc(C#CCOCCOCCOCCOCCO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 3-iodobenzoate (25.68 g, 66.19 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), 2-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)ethanol (15.36 g, 66.21 mmol, 1.00 equiv), copper(I) iodide (1.26 g, 6.63 mmol, 0.10 equiv), Pd(PPh3)2Cl2 (4.65 g, 6.62 mmol, 0.10 equiv), triethylamine (13.4 g, 132.67 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (1:1). This resulted in 20 g (68%) of benzyl 3-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)prop-1-ynyl)benzoate as a brown oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][C:37](=O)[CH2:36]1)=[O:34])[CH3:31]>C(O)(=O)C.C1COCC1>[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][CH:37]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:36]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1CC(=O)C1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
Dibenzyl amine (0.150 g, 0.77 mmol) and sodium triacetoxyborohydride (0.300 g, 1.4 mmol) were added to a solution of 3-oxo-cyclobutanecarboxylic acid ethyl ester (0.100 g, 0.700 mmol) and acetic acid/THF (10%, 4.4 mL), stirred at room temperature for 72 hours and concentrated in vacuo. The resulting residue was dissolved in dichloromethane, washed with water, saturated NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo to give crude product. Purification by flash chromatography (silica, 1:9-3:7 EtOAc:hexanes) provided the title compound (0.180 g, 73% yield, 10:1 cis:trans ratio) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:17]([C@@:11]1([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:12][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)[CH3:18]
Reactant: CC[C@@]1(C(=O)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of (1R,3S)-3-[(tert-butoxycarbonyl)amino]-1-ethylcyclopentanecarboxylic acid (0.30 g, 1.2 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (0.39 g, 1.3 mmol) in DMF (10 mL) under N2 was added triethylamine (0.65 mL, 4.7 mmol) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.663 g, 1.75 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (400 mg, 72.9%). MS calculated for C23H34F3N4O3:(M+H) 471.3; found 371.2 (M+H-Boc).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]3[N:18]([N:28]=[C:29]([C:31]([NH2:33])=O)[CH:30]=3)[C:19](=[O:27])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]3[N:18]([N:28]=[C:29]([C:31]#[N:33])[CH:30]=3)[C:19](=[O:27])[C:20]=2[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Reaction time: 2.5 h
Yield: 14.1 %

Procedure:
To a mixture of 22 mg (0.05 mmol) of 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid amide in 1 mL of dichloromethane (DCM) was added 0.04 mL (0.3 mmol) of triethylamine (Et3N), and the resulting mixture was cooled in an ice bath. Then 0.021 mL (0.15 mmol) of trifluoroacetic anhydride ((CF3CO)2O) was added during which time the mixture became homogeneous, and was stirred for 2.5 h. The reaction mixture was quenched by the addition of water, and concentrated to a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 3 mg (14% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carbonitrile as indicated by LC-MS calcd for C26H24N4O2 [M++H]+: 425.19, found: 425.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N:12]1([C:17]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=2[NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:17]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCC1)c1cc(Br)ccc1O
Yield: 44.5 %

Procedure:
Using 5-bromosalicylic acid and 2-(1-pyrrolidinyl)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Br:1][CH2:2][C@H:3]([CH3:11])[O:4]C1C[CH2:9][CH2:8][CH2:7][O:6]1.[Br:12]C[C@@H](O)C>ClCCl.C(O)(=O)C>[Br:1][CH2:2][C@@H:3]([OH:4])[CH3:11].[CH2:7]1[O:6][C@H:8]1[CH3:9].[BrH:12]
Reactant: C[C@@H](CBr)OC1CCCCO1
Agent: C[C@H](O)CBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: Br
Product: C[C@H]1CO1

Procedure:
The manner in which optically active forms of arylmethoxy aliphatic amines, such as (2S)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine type compounds, are providcd can vary. In one approach, a 3-aminobenzyl alcohol type compound (N-protected as the phthalimide) can be alkylated with a chiral 1-bromo-2-propanol type compound containing an O-protecting group, such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran using a base such as sodium hydride and a solvent such as N,N-dimethylformamide or tetrahydrofuran. The tetrahydropyranyl protecting group of the resulting chiral arylmethyl ether type compound can be removed with aqueous sulfuric acid in methanol, affording (2S)-1-[(3-aminophenyl)methoxy]-propan-2-ol. The resulting chiral alcohol intermediate can be converted to its corresponding tosylate, followed by tosylate displacement with methylamine with inversion of configuration, and finally removal of the N-phthaloyl group to give the chiral amine (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine. Chiral side chain compounds such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran can be prepared from (2S)-1-bromo-2-propanol by treatment with 3,4-dihydro-211-pyran in dichloromethane with p-tolucnesulfonic acid as a catalyst according to the method of S. A. M. Nieuwenhuis et al., Tetrahedron 50: 13207-13230 (1994). The required (2S)-l-bromo-2-propanol can be obtained from (S)-propylene oxide (commercially available from Fluka) by treatment with hydrogen bromide in acetic acid at 0° C. The corresponding optical antipode, (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine can be prepared in an analogous manner from (R)-propylene oxide (commercially available from Fluka) by using the synthetic procedure of S. A. M. Nieuwenhuis et al. to prepare the tetrahydropyranyl ether of (2R)-1-bromo-2-propanol and by using the synthetic sequence described above.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C[O-].[Na+].[CH2:14]([O:16][CH:17]([O:22][CH2:23][CH3:24])[C:18](=[NH:21])OC)[CH3:15]>CO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:18](=[NH:21])[CH:17]([O:22][CH2:23][CH3:24])[O:16][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: CCOC(OCC)C(=N)OC
Reactant: NCc1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Br)cc1
Yield: 62.3 %

Procedure:
(4-Bromophenyl)methanamine hydrochloride (2.359 g, 10.39 mmol) and sodium methoxide (2.376 mL, 10.39 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (3.35 g, 20.78 mmol) in methanol (10 ml). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel with 100% ethyl acetate to give a yellow viscous oil (2.04 g, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (2H, d, J=8.56 Hz), 7.23 (2H, d, J=8.06 Hz), 6.76 (1H, br. s.), 5.31 (1H, br. s.), 4.94 (1H, br. s.), 4.45 (2H, br. s.), 3.47-3.77 (4H, m), 1.26 (6H, t, J=7.05 Hz). LCMS:R.T.=2.12; [M+2]+=317.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][N:10]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(F)ccc2F)nc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To tert-butyl 6-(2,5-difluorophenyl)nicotinate in DCM (12 mL) at 0° C. was added TFA (5 mL). After stirring at room temperature overnight, toluene was added (10 mL) and the solvent removed to give a white solid (176 mg, 97%), 6-(2,5-difluorophenyl)nicotinic acid. LC/MS (M+H)=236.0 observed, 236.05 expected
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1.CCCCCC>[OH:17][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC1(O)c1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-2-(trifluoromethyl)benzene (0.27 mL, 2.0 mmol) in THF (5 mL) at −78° C. was added nBuLi (0.72 mL of a 2.8 M solution in Hexane, 2.0 mmol). The reaction was stirred at −78° C. for 15 minutes then added to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (0.33 mL, 2.0 mmol) in THF (5 mL) at −78° C. The reaction was stirred to room temperature over 1 hour, quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and reduced to dryness to afford tert-butyl 2-hydroxy-2-(2-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate (I-27) as a clear oil. MS m/z 276.1 (M−55)+.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]2([CH2:12][O:11][P:10](Cl)[O:9][CH2:8]2)[CH2:4][O:3]1.[CH2:14]([NH2:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([N:35]([CH2:38][CH3:39])CC)C>C1(C)C=CC=CC=1>[CH2:14]([NH:32][P:2]1[O:7][CH2:6][C:5]2([CH2:12][O:11][P:10]([NH:35][CH2:38][CH2:39][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[O:9][CH2:8]2)[CH2:4][O:3]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNP1OCC2(CO1)COP(NCCCCCCCCCCCCCCCCCC)OC2
Yield: 90.3 %

Procedure:
The procedure of Example 1 is repeated using 13.3 g (50 mmol) of 3,9-dichloro-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane, 27.1 g (100 mmol) of octadecylamine and 15 mL (110 mmol) of triethylamine in 350 mL of toluene to give a crude reaction residue. The residue is purified by recrystallization from a mixture of toluene and acetonitrile to give 33 g (90% yield) of the title compound as an off-white solid melting at 67°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:48]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:48]=2)=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, a solution of ethyl (2-amino-4-thiazolyl)acetate (76 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 22 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][N:3]=1.[OH:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13].C(N(CC)CC)C.C1C[O:30]CC1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[OH:10])=[O:30])=[CH:4][N:3]=1
Reactant: C1CCOC1
Reactant: ClCc1ccc(Cl)nc1
Reactant: COc1ccc(N)c(O)c1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloronicotinyl chloride (2.0 g, 11.4 mmol) in THF (10 mL) was added dropwise to a mixture of 2-hydroxy-4-methoxyaniline (1.58 g) and triethylamine (1.8 mL) in THF (20 mL) at r.t. The reaction was stirred at r.t for 30 minutes and was then heated to reflux for 5 minutes. After cooling to r.t. the solid was collected, rinsed with water, dried (under vacuum over P2O5), to give the title compound (1.77 g) as an orange solid. 1H NMR δ ppm 9.78 (br. s, 1H) 9.63 (br. s, 1H) 8.94 (d, 1H) 8.34 (dd, 1H) 7.68 (d, 1H) 7.34 (d, 1H) 6.49 (d, 1H) 6.42 (dd, 1H) 3.71 (s, 3H); MS m/z (M+H) 279, 281; (M−H) 277, 279.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28](Cl)[N:27]=[C:26]([NH2:31])[N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCCCCC.CCOC(C)=O>CO.[Pd]>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH2:31])[N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nccc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1

Procedure:
Hydrogenation of 0.26 g (0.54 mMol) 7-(2-amino-6-chloro-pyrimidin-4-yloxy)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 15 ml methanol in the presence of 70 mg Pd/C (Engelhard 4505), filtration and column chromatography (SiO2; hexane/EtOAc 3:2→2:3) of the filtrate gives the title compound: m.p.: 207° C.; MS: [M+1]+=444/480; Anal.: C,H,N,F.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH2:26]>>[ClH:1].[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:3]=1
Reactant: NCC(O)CN
Reactant: Clc1cc(-c2ccc3ccccc3c2)nc2ccccc12
Product: Cl
Product: NCC(O)CNc1cc(-c2ccc3ccccc3c2)nc2ccccc12

Procedure:
The title compound, m.p. 288-291° C., MS: m/e=343 (M+), was prepared 4-chloro-2-naphthalen-2-yl-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.ClC1N=CC=CC=1C(Cl)=O.[Cl:25][C:26]1[C:31]([NH2:32])=[C:30]([CH3:33])[CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[C:3]([C:4]([NH:32][C:31]2[C:26]([Cl:25])=[N:27][CH:28]=[CH:29][C:30]=2[CH3:33])=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C(Cl)c1cccnc1Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl

Procedure:
In the method of Hargrave et al., 2-chloronicotinoyl chloride is formed by reacting 2-chloronicotinic acid with thionyl chloride. Next, as shown in Scheme 1, the reaction of 2-chloronicotinoyl chloride with 2-chloro-4-methyl-3-pyridinamine produces 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide. This is reacted with cyclopropylamine to give N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide. The final step is the cyclization to produce nevirapine, which occurs on treatment of the final intermediate with sodium hydride.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:38]=[N+:39]=[N-])(=O)=O)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([C:13](=[N+:38]=[N-:39])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To methyl 3,5-bis(trifluoromethyl)phenylacetate (43.5 g, 160 mmol), in dry acetonitrile (250 ml), cooled to -5° C., was added 2,4,6-triisopropylbenzenesulfonyl azide (52.7 g). To the resulting solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.5 ml), and the mixture was stirred at -5° C. for 1 hour. The mixture was warmed to room temperature, and then stirred for 0.5 hour. The solvents were evaporated at reduced pressure and the residue chromatographed on silica (eluent 5% ether/60-80 bp petrol), to afford the the title compound (45.6 g, 91%) as yellow prisms. I.R (film, NaCl) n 1740, 2140 cm-1.